In anesthesia, neuromuscular blocking agents are used to provide skeletal muscular relaxation during surgery and during intubation of the trachea.
In general there are two types of neuromuscular blocking agents in use, nondepolarizing and depolarizing.
The nondepolarizing agents include d-tubocurarine, pancuronuim gallamine, diallyltoxiferine, and toxiferine.
The depolarizing agents include succinylcholine and decamethonium. All of the conventional nondepolarizing agents when used for producing skeletal muscle relaxation in surgery have a long duration of action e.g., 60 to 180 minutes in man.
The depolarizing agents on the other hand provide muscle relaxation at dosages normally used for surgery which is less than the duration of action of nondepolarizing agents.
For example, succinylcholine provides a short duration of action of about 5 to 15 minutes whereas decamethonium provides about 20 to 40 minutes duration of muscle relaxation.
To the best of applicants' knowledge, there are no nondepolarizing agents currently available for approved clinical use which have a short duration of action.
As used herein a short duration of action is defined as less than about 10 minutes in the monkey.
The long duration of action of nondepolarizing agents is unacceptable in many surgical procedures which take less than one hour because the patient is not generally fully recovered from their effects e.g., the patient may be unable to breathe adequately on his or her own.
Each nondepolarizing agent has inherent side-effects. For example, gallamine and pancuronium may cause tachycardia, and d-tubocurarine and diallyltoxiferine may cause hypotension.
While such drugs can be pharmacologically antagonized with anticholinesterase agents, this obviously necessitates the administration of a second drug which itself may have its own side effects e.g., bradycardia, gut spasm and bronchorrhea. Thus, to overcome the aforementioned side effects of the anticholinesterase agents, a third drug, an anticholinergic drug e.g., atropine must also be given.
The depolarizing agents to the best of applicants' knowledge have no pharmacologic antagonists. While in most cases there is no need to reverse the effects of the depolarizing agents, in certain patients the effects of succinylcholine are much prolonged because of abnormal metabolism of the agent by the patient.
The depolarizing agents due to that mode of action which initially causes skeletal muscle contraction and stimulation of smooth muscles are also known to cause the following side effects in certain instances: increased intraocular, and intragastric tension, cardiac arrhythmias, potassium release, and muscle pain.
These side effects caused by the depolarizing agents are not caused by the nondepolarizing agents. It is therefore clearly evident that a new neuromuscular blocking agent is needed which would combine the short duration of action of the depolarizing agents with the relatively few side effects and the reversibility of the nondepolarizing agents.
It should be understood that while nondepolarizing agents generally have few side effects, gallamine and pancuronium may cause tachycardia and d-tubocurarine and diallyltoxiferine may cause hypotension.
Surprisingly, the compounds of the present invention also appear to be free of these side effects at the dosages anticipated being used clinically in tests made to date. Reference may be had to the text of:
"The Pharmacological Basis of Therapeutics"--Fifth Edition, edited by Louis S. Goodman and Alfred Gilman published by The McMillian Co., copyright 1975, Chapter 28, author George B. Koelle, for further description of neuromuscular blocking agents.
Reference should also be had to the following articles:
"Neuromuscular Blocking Activity of a New Series of Quaternary N-Substituted Choline Esters"--British Journal of Pharmacology, Sept., 1971, vol. 43, No. 1, p. 107; PA1 "The Pharmacology of New Short Acting Nondepolarizing Ester Neuromuscular Blocking Agents: Clinical Implications"--published in Anesthesia and Analgesia . . . Current Researches, Vol. 52, No. 6, p. 982, Nov.-Dec., 1973; PA1 "Potential Clinical Uses of Short-Acting Nondepolarizing Neuromuscular-Blocking Agents as Predicted from Animal Experiments"--published in Anesthesia and Analgesia . . . Current Researches, Vol 54, No. 5, p 669, Sept.--Oct., 1974; and PA1 U.S. Pat. No. 3,491,099, for a further description of neuromuscular blocking agents. PA1 R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are the same or different and are hydrogen or alkoxy of 1 to 4 carbon atoms, (methoxy, ethoxy, propoxy or butoxy). PA1 Y is alkyl of 1 to 4 carbon atoms (methyl, ethyl, propyl or butyl), PA1 n is 2, 3 or 4 most preferably 3 and X is a pharmaceutically acceptable anion, provided that at least one of R.sub.1 to R.sub.4 is always lower alkoxy and at least one of R.sub.5 to R.sub.7 is always lower alkoxy. The preferred compounds of this invention are those in which R.sub.5 to R.sub.7 are each lower alkoxy.